Synthesis of all-cis -1,2,4-cyclohexanetriol

A one step synthesis of (±)-all- cis -1,2,4-cyclohexanetriol 1 by high pressure hydrogenation of the corresponding 1,2,4-benzenetriol in the presence of Raney-nickel or a catalytic amount of rhodium on aluminium oxide is disclosed.


Introduction
Polyhydroxycyclohexanes are of great interest as model compounds for studies in carbohydrate chemistry and stereochemistry, and are of importance because of their relationship to the biologically important cyclitol and myo-inositol. 1n the literature, 2 an extensive study on the synthesis and conformational NMR-analysis of the series of nine isomeric cyclohexanetriols (there are 14 cyclohexanetriol isomers if the two enantiomers of each racemic pair are separately counted) was performed.For cyclohexanetriol, three structures are possible: cyclohexane-1,2,3-triol (vicinal); cyclohexane-1,3,5-triol (symmetric), and cyclohexane-1,2,4-triol (asymmetric).cis-1,2,4-Cyclohexanetriol 1 is a target molecule for the synthesis of the corresponding orthoester derivatives, which are the "core" of resiniferatoxin 2 (Figure 1), isolated from Euphorbia resinifera. 3Resiniferatoxin acts as an ultrapotent analogue of capsaicin, the pungent constituent of hot peppers. 4Both of the latter substances possess the ability to excite and subsequently desensitize sensory nociceptor neurons, leading to analgesia. 5

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Because of the potential importance of a readily available source of racemic all-ciscyclohexane-1,2,4-triol 1 as basic core of the daphnane diterpenes family, potent tumor promoters, 8 and cage orthoesters, as present in resiniferatoxin (RTX) and various other esters of resiniferonol, 9 a short synthesis of triol 1 was developed.
High pressure hydrogenation of 1,2,4-trihydroxybenzene 3 at 100 atmospheres was performed with Raney-nickel in ethanol at 100°C (Scheme 1).The workup of the reaction mixture obtained was not easy because of the high viscosity and the water solubility of the reaction products.After filtration, the viscous reaction mixture was preferably quickly distilled under high vacuum and, successively, the complex reaction mixture was separated by flash chromatography on silica gel affording the pure (±)-all-cis-cyclohexane-1,2,4-triol 1 in 31 % yield.The other compounds isolated by flash chromatography were trans-cyclohexane-1,2-diol 4, and cyclohexane-1,4-diol 5, both in a minor yield of 5 % (Scheme 1).
To avoid substantial loss of the triol 1 during the silica gel chromatography, the separation of the reaction mixture was performed also by centrifugal counter current chromatography (Centrifugal CCC).The yield of the triol 1 could not be improved higher than 30 %.This represents an alternative way for the isolation of the (±)-all-cis-cyclohexane-1,2,4-triol 1.
To improve the results of the catalytic hydrogenation, other metals were used for this high pressure reaction.The hydrogenation reaction of trihydroxy-1,2,4-benzene 3 was performed with rhodium on aluminium oxide (5 %) as catalyst in tetrahydrofuran at 100 atmospheres of pressure (Scheme 2).The same complex mixture of isomers was obtained, but with the (±)-all-cis-1,2,4cyclohexanetriol 1 as predominant compound.The high pressure was necessary for the completion of the reaction.In fact, the same reaction with Rh/Al 2 O 3 performed at one atmosphere of pressure gave, after one week at 50°C, a reaction mixture in which the main compound was still the 1,2,4-trihydroxybenzene 3. Using Rh/Al 2 O 3 as catalyst, the high vacuum distillation of the reaction mixture was not necessary, and the mixture of reaction products was immediately separated by flash chromatography on silica gel, affording the desired all-cis-triol 1 in an improved yield of 50 %.

Experimental Section
General Procedures.NMR spectra were run on a JEOL JNM EX 270 spectrometer, using CD 3 OD as the solvent.TLC was performed on Si gel plates Kieselgel 60F 254 .Flash chromatography was carried out on Si gel (Merck; particle size 40-63 µm).Raney-nickel, Rh/Al 2 O 3 , and 1,2,4-trihydroxybenzene were of commercial grade (Aldrich or Acros) and used without further purification.
The high pressure hydrogenation reaction with Rh/Al 2 O 3 was performed in an analogous way as the procedure described with Raney-nickel.The only difference was the amount of rhodium on aluminium oxide used in a catalytic amount (0.5 g of Rh/Al 2 O 3 for 10 g of 1,2,4trihydroxybenzene).After filtration and evaporation of the solvent, the mixture of reaction products obtained was separated by flash chromatography on silica gel using a mixture of CH 2 Cl 2 /MeOH (4:1) to give compound 1 in 50 % yield.